CLEARANCE OF ABETA

last modification: December 2004

- Once formed, Abeta is mainly broken down by neprilysin 

(Yasojima K, McGeer EG, McGeer PL (2001) Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain. Brain Res, 919, 115-21)

 Mice knock out with neprelysin gene are not able to clear Abeta.

- IDE (insulin degrading enzyme) appears to degrade intracellular Abeta more effectively than does NEP  Biochemistry. 41(4): 1091-9, 2002

-Plasmin is also a good candidate

Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer's disease brains.
EMBO Rep. 2000 Dec;1(6):530-5.
PMID: 11263499 [PubMed - indexed for MEDLINE]

Plasmin is derived from its inactive precursor plasminogen by the action of two proteases: tissue-type and urokinase plasminogen activators (tPA and uPA, respectively). Interest in a possible association between AD and uPA was sparked in 2000, when two independent groups led by Alison Goate and Steve Younkin reported linkage to a region of chromosome 10 (possibly distinct from the IDE locus) that contains the gene for uPA (PLAU). The Younkin group reported significant linkage between a subset of AD cases and certain haplotypes of SNPs near the PLAU gene (Ertekin-Taner et al., Abstract 1169). This same group also found that uPA knockout mice exhibit significantly elevated Ab levels in plasma, but not in brain, in an age-dependent fashion. Finally, tissue-type plasminogen activator knockout mice were reported at the Stockholm meeting to show decreased clearance of  Ab (Denis Vivien et al, Rouen, France).

Tucker HM, ... , Estus S. Urokinase-type plasminogen activator inhibits amyloid-beta neurotoxicity and fibrillogenesis via plasminogen., J Neurosci Res  2002 Oct;70(2):249-55

- Endothelin-converting enzyme-1, a protease belonging to the same class as neprilysin  was shown by Chris Eckman and colleagues to degrade Ab in vitro (Eckman et al, 2001).

Abeta can be captured by macrophages

Yazawa H, Yu ZX, Takeda, Le Y, Gong W, Ferrans VJ, et al. (2001) Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. Faseb J, 15, 2454-62.

Microglial reaction is important to remove Abeta aggregates: see vaccination

PubMed Abstract

Although PPARgamma expression is generally low in the CNS, induction of PPARgamma expression during inflammation could be beneficial for inducing Abeta clearance.

Abad-Rodriguez J, Neuronal membrane cholesterol loss enhances amyloid peptide generation., J Cell Biol  2004 Dec;167(5):953-60 PubMed Abstract

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Kaether C, A lipid boundary separates APP and secretases and limits amyloid {beta}-peptide generation., J Cell Biol  2004 12;167(5):809-812 PubMed Abstract